Cholecystokinin (CCK) is a gut peptide produced by CCK cells located in the duodenum and proximal jejunum. The major dietary intestinal stimuli for its release are intact proteins and fatty acids. Recent observations suggest that this gut peptide may serve a far more fundamental purpose than simply coordinating digestion of a meal. It has been shown that CCK is capable of maintaining gastric mucosal Integrity In the face of a damaging luminal insult. Consequently, it seems likely that nutrients contained within an Ingested meal stimulate the release of gut peptides, such as CCK, that not only coordinate the digestive process, but also promote intestinal health and render the gut more resistant to damage from luminal irritants that often accompany a meal. Gastric injury from excessive alcohol consumption or ingestion of aspirin continues to be a major cause of upper gastrointestinal bleeding. Further, gastric ulceration remains a major clinical problem. Thus, the overall HYPOTHESIS of this research proposal is that dietary intestinal nutrients elicit the release of endogenous CCK and through such release, enables the gastric epithelium to become more resistant to injury from potentially damaging luminal challenges that would otherwise occur. The precise conditions by which CCK mediates its protective effects as well as the mechanism(s) responsible for these actions remain to be fully elucidated. This being the case, the present research proposal will address the following five specific aims. The first aim will be to characterize the conditions under which exogenous CCK prevents gastric injury. The second aim will be to determine whether nutrient induced release of endogenous CCK alters the ability of the gastric epithelium to maintain its integrity in response to a damaging insult. The third aim will ascertain the role that gastric mucosal blood flow plays in nutrient induced gastric protection. The fourth aim will elucidate the effects of exogenous CCK on gastric epithelial ion transport as a potential protective mechanism. The fifth aim will examine the effects of nutrients on gastric Na+, K+ ATPase activity. The results of this research proposal will clarify the importance of nutrients in the intrinsic gastric mucosal defense system and enhance our understanding of the physiological function of the endogenous gut peptide, CCK.